The National Cancer Institute (NCI) initially suspended the enrollment of patients in the Treatment Referral Center Protocol of Bevacizumab (Avastin™) for Metastatic Colorectal Cancer on October 31, 2003, because the study had reached its initial accrual goal. Per the study protocol, enrollment was suspended until sufficient evidence of anti-tumor activity was demonstrated or bevacziumab became commercially available. Based on a preliminary interim analysis in early February 2004, there did not appear to be sufficient evidence of efficacy to warrant re-opening the trial to additional accrual. When the U.S. Food and Drug Administration (FDA) approved bevacizumab on February 26, 2004, and the agent became commercially available, the study was permanently closed to accrual. Additional information on the preliminary study results is provided in the ASCO abstract of the study [Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 3515] and in a slide presentation of the preliminary trial results at TRCPslides.pdf .

1. What is bevacizumab?

   Bevacizumab, whose brand name is Avastin™, is an investigational drug. It is a monoclonal antibody (a substance formed in a laboratory that can locate and bind to cancer cells wherever they are in the body) produced from genetically engineered cells. Bevacizumab is designed to specifically block the action of a protein called vascular endothelial growth factor (VEGF). Bevacizumab belongs to a family of drugs called antiangiogenic agents, or angiogenesis inhibitors. Angiogenesis inhibitors prevent the formation of new blood vessels that surround and "feed" cancer cells the oxygen and nutrients they need to grow. By depriving cancer cells of their blood supply, angiogenesis inhibitors may be able to reduce tumor cell growth and cause cancerous tumors to grow more slowly or to become smaller.

2. What is a Treatment Referral Center Protocol?

   A Treatment Referral Center (TRC) Protocol is a mechanism by which the National Cancer Institute makes an investigational drug available at NCI-designated Clinical and Comprehensive Cancer Centers and other institutions selected to provide wide geographic availability. A TRC protocol is established when clinical evidence suggests that a new agent should be made more widely available to patients even though it is not yet approved by the FDA. FDA approval for this drug did occur on February 24, 2004.

3. What was the purpose of the TRC Protocol?

   The main objective of this trial was to find out whether the addition of bevacizumab to fluorouracil and leucovorin calcium would be effective and safe in patients with advanced colorectal cancer that had progressed after standard chemotherapy. The study was initially designed in two parts. The first part was designed as a standard Phase II trial, and recruited 125 patients to assess the effectiveness of the treatment regimen. Patient enrollment was suspended after the first part to adequately assess activity and safety. If the regimen had been active and an acceptable safety profile was obtained in this group of patients, the trial would have opened the second part, in which more patients could have been be enrolled to receive this treatment regimen.

4. Who participated in the study?

   This study was specifically designed for people who already had treatment with oxaliplatin- and irinotecan-containing chemotherapy regimens and who were no longer benefitting from these treatments. Treatment for patients who have already had two different forms of treatment is known as "third-line" therapy.

5. What did the treatment in this study involve?

   Participants in this study received the investigational agent, bevacizumab, in combination with 5-fluorouracil (5-FU) and leucovorin. The drugs were given in a treatment cycle that was 8-weeks long. (It should be noted that most patients who were eligible for this study would have had 5-FU and leucovorin during previous treatment and, therefore, would be unlikely to benefit from more chemotherapy alone.) Patients who benefitted from their first 8-week treatment cycle received treatment as long as they continued to benefit. Benefit is defined as a complete response (disappearance of tumors), a partial response (significant shrinkage of tumors), stable disease (no significant shrinkage or growth), and no new tumors. Patients who did not benefit from the initial or subsequent treatment cycles stopped this study regimen and were counseled about other options.

6. How did doctors know if study participants were benefitting from the new treatment?

   The doctors monitored participants closely to track changes in their tumors and to check their general health. Monitoring procedures included chest X-rays, computed tomography (CT or CAT) scanning, and/or magnetic resonance imaging (MRI). For tumors that could be seen and felt on the skin or in lymph nodes, the study staff used a ruler and color photography. Participants also had lab tests and physical examinations.

7. Why did the doctors think this drug combination might work?

   In a large "first-line" therapy trial (involving people who had not yet received treatment for their metastatic colorectal cancer), investigators saw longer survival and tumor control among those who received bevacizumab along with a standard chemotherapy called IFL (irinotecan, 5-FU, and leucovorin) than among those who received IFL without bevacizumab.

8. Does bevacizumab cause side effects?

   In earlier trials, most patients tolerated bevacizumab well, although serious adverse events have been observed. Side effects can include high blood pressure, nose bleeds, fever, headache, rash, and chills. In addition, this bevacizumab may be associated with blood clots and bleeding, which can be life-threatening. In rare cases, bevacizumab increased the risk of other life-threatening complications such as perforation of the wall of the colon.

9. Where did the study take place?

   The TRC protocol was carried out at NCI-designated Cancer Centers, as well as at certain other institutions, to ensure wide geographic availability.

10. Who sponsored the study?

    The NCI's Cancer Therapy Evaluation Program (CTEP) sponsored this trial in collaboration with Genentech Inc., the manufacturer of bevacizumab.

11. Are other treatments available to patients with advanced colorectal cancer?

    Some patients with advanced colorectal cancer may be eligible to participate in other clinical trials. Links to listings of ongoing trials for advanced colorectal can be found at http://cancer.gov/clinicaltrials on the Internet. Other patients may decide to have no further cancer therapy and to receive only therapy to control their symptoms.

12. When did the study begin? When did it end?

    The study began in July 2003 after the first participating institution received approval from its Institutional Review Board (IRB). The study had two parts. The first part was intended to evaluate 125 patients to see if the treatment regimen was useful. Enrollment to this first part was completed on October 31, 2003. Based on an interim analysis in early February 2004, there did not appear to be sufficient evidence of efficacy to warrant re-opening the trial to additional accrual. The FDA approved commercial use of bevacizumab on February 26, 2004, and the study was permanently closed to accrual.

13. Did patients have to pay for their treatment in the Treatment Referral Center Protocol?

    NCI provided bevacizumab to study participants free of charge through an agreement with the bevacizumab manufacturer, Genentech Inc. Patients or their insurers, however, will have to pay for the other drugs and the costs associated with their treatment. Patients should check with their insurer about coverage of these costs before they begin treatment.

14. Where can patients find out more about their disease and its treatment?

    Patients can find out more about colorectal cancer and its treatment by contacting the National Cancer Institute's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). For callers with TTY equipment, the number is 1-800-332-8615. The NCI's Cancer.gov Web site also provides information about colorectal cancer at http://colon.cancer.gov and about clinical trials at http://cancer.gov/clinical_trials

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    To view the Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 3515, please go to: http://meeting.jco.org/cgi/content/abstract/22/14_suppl/3515.

    To view a slide presentation of the preliminary trial results of this study, please go to TRCPslides.pdf.

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